Nutrient responsive glycosylation of nuclear and cytoplasmic proteins with O-linked N-acetylglucosamine (O-GlcNAc) is an abundant protein modification within mammalian brains. O-GlcNAc transferase (OGT) acts to install O-GlcNAc on serine and threonine residues of target proteins whereas the glycoside hydrolase O-GlcNAcase (OGA) removes this modification. O-GlcNAc levels have been found to be decreased in the brains of Alzheimer disease (AD) patients, which is consistent with the early impairment in glucose metabolism that is known to occur in this neurodegenerative disease. Decreases in protein O-GlcNAcylation have been proposed as a factor contributing to the progression of AD. In this presentation I will discuss our research directed at generating brain permeable inhibitors of OGA. Our recent observations regarding the structure-activity relationships of various potent and selective OGA inhibitors will be described. I will finally touch on our preclinical animal studies, through which we have provided proof-of-concept for OGA inhibition as a promising approach that could yield a disease modifying therapy for AD.

Generation of brain active O-GlcNAcase inhibitors for use in preclinical animal models

251st National Meeting (2016)

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